Monoclonal Antibody Therapies for Hematological Malignancies: Not Just Lineage-Specific Targets

Abstract

Today, monoclonal antibodies (mAbs) are a widespread and necessary tool for biomedical science. In the hematological cancer field, since rituximab became the first mAb approved by the Food and Drug Administration for the treatment of B-cell malignancies, a number of effective mAbs targeting lineage-specific antigens (LSAs) have been successfully developed. Non-LSAs (NLSAs) are molecules that are not restricted to specific leukocyte subsets or tissues but play relevant pathogenic roles in blood cancers including the development, proliferation, survival, and refractoriness to therapy of tumor cells. In consequence, efforts to target NLSAs have resulted in a plethora of mAbs—marketed or in development—to achieve different goals like neutralizing oncogenic pathways, blocking tumor-related chemotactic pathways, mobilizing malignant cells from tumor microenvironment to peripheral blood, modulating immune-checkpoints, or delivering cytotoxic drugs into tumor cells. Here, we extensively review several novel mAbs directed against NLSAs undergoing clinical evaluation for treating hematological malignancies. The review focuses on the structure of these antibodies, proposed mechanisms of action, efficacy and safety profile in clinical studies, and their potential applications in the treatment of hematological malignancies.

Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents

“…Talacotuzumab (TAL, JNJ-56022473) is an IgG1 monoclonal antibody targeting CD123 preferentially via antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells [9] and has been shown to induce potent in vitro ADCC against IL3RA-expressing AML blasts/LSC and to reduce leukemic cell growth in murine xenograft models of human AML [10]. In addition, the antibody inhibits signaling by IL-3, the main ligand of CD123, to reduce the proliferation of leukemic progenitor cells [11].…”

Multiplex Three-Dimensional Mapping of Macromolecular Drug Distribution in the Tumor Microenvironment

“…Recent advances in biology (41), immunology (42), and chemistry (43) have enabled dramatic progress in the development of biologics and other macromolecular drugs as targeted cancer therapeutics. Similar progress has been made in nanomedicines.…”

Monoclonal antibodies in the treatment of AL amyloidosis: co‐targetting the plasma cell clone and amyloid deposits

“…Haematological malignancies are convenient for the use of monoclonal antibodies because of tumour cell accessibility. Starting in 1997 with the approval of the first mAb rituximab for use in haemato‐oncology, this branch of targeted therapy has proved to dramatically enhance oncological treatment, bringing high specificity together with minimal off‐site toxicity (Cuesta‐Mateos et al , ).…”

“…This surface glycoprotein, located on chromosome 1q23, is expressed by normal plasma cells and cytolytic lymphocyte subsets such as natural killer (NK) cells, natural killer T (NKT) cells or CD8 + T cells. Clonal plasma cells are often impaired by 1q23 amplification, proposing SLAMF7 for targetted therapy (Cuesta‐Mateos et al , ). Its mechanism of action is mainly via NK‐cell‐mediated ADCC.…”